The clinical relevance of Th17 cells is recently highlighted by the remarkable efficacy of anti-IL-17 antibodies in treating Psoriasis, Ankylosing spondylitis and Multiple sclerosis. Not all Th17 cells are pathogenic and in some autoimmune diseases (eg. IBD), anti-IL-17 antibodies made disease worse, highlighting the importance of selectively targeting pathogenic but spare protective Th17 cells. Costimulatory receptors and their ligands have a profound impact on autoimmune diseases by regulating the balance between pathogenic (Th1 and Th17) and protective (Treg) cell types. The role of inhibitory molecules in Th17 cell pathogenicity has not been fully explored. Using a temporal whole genome transcriptional approach, we have identified modules that positively or negatively regulate Th17 cell development as well as a signature that represents Th17 cells that can induce autoimmunity (pathogenic) and those that cannot (non-pathogenic). Among these molecules, a novel inhibitory molecule, PROCR (Protein C Receptor), emerged as selectively enriched on non-pathogenic Th17 cells. Similar to the well-known inhibitory molecule PD-1, PROCR can promote Th17 cell differentiation but once expressed inhibit effector functions of Th17 cells. We hypothesize that PROCR and PD-1 can influence the generation of pathogenic Th17 cells and thus regulate the development of autoimmune diseases. We propose these specific aims to address this hypothesis: 1: Study how PD-1 and PROCR regulate induction and effector functions of Th17 cells. Since both PD-1 and PROCR are co-inhibitory receptors, we propose that they do not only inhibit Th17 cells but also promote differentiation of non-pathogenic Th17 cells. Using PD-1-/- and PROCRd/d mice, we will analyze whether the two molecules synergize to affect Th17 development, function and whether they regulate the development of ectopic lymphoid follicles, a hallmark of Th17-induced chronic autoimmunity. 2: Determine the role of ligands of PROCR and PD-1 in limiting Th17 cell pathogenicity. Activated protein C (aPC), one of the known ligands for PROCR, has both anti-coagulant and anti-inflammatory effects. We have obtained a number of aPC mutants with selected functions and are beginning to test their ability to convert pathogenic Th17 cells into non-pathogenic Th17 cells and whether they synergize with PD-1 ligands to inhibit Th17 cell pathogenicity and alter clinical course of established autoimmune diseases. 3: Reconstruct the dynamic regulatory network to define the pathways by which PD-1 and PROCR control development and effector functions of Th17 cells. Since we have built a transcriptional network that controls development of Th17 cells, we are in a unique position to study how loss of PD-1 and PROCR will affect the network of Th17 cell differentiation and effector output. We will study how perturbation of key nodes in the PD-1 and PROCR pathway may change the Th17 cell fate and test their relevance using the EAE model.